Pembrolizumab continues to demonstrate meaningful efficacy and a manageable safety profile in sorafenib-treated patients with advanced hepatocellular carcinoma, according to an additional 18 months of follow-up.
The KEYNOTE-240 clinical trial previously found that the anti-programmed death-1 antibody pembrolizumab had demonstrated improvement in overall survival (OS) and progression-free survival (PFS) compared to placebo in patients with advanced hepatocellular carcinoma previously treated with sorafenib.
"However, the study did not meet pre-specified statistical significance criteria for OS and PFS," said lead author Philippe Merle, MD, PhD, Professor of Hepato-Gastroenterology and Digestive Oncology in the Centre of Research in Cancerology at Lyon University and Croix-Rousse Hospital in France, while presenting his research at the 2021 ASCO Gastrointestinal Cancers Symposium.
At final analysis, median OS was 13.9 months for pembrolizumab versus 10.6 months for placebo. At the first interim analysis when PFS and overall response rate (ORR) were pre-specified to be tested, median PFS was 3.0 months for pembrolizumab versus 2.8 months for placebo, and ORR was 16.9 percent (three patients with complete responses [CR]) for pembrolizumab and 2.2 percent (no CRs) for placebo. Adverse events were consistent with the known safety profile of pembrolizumab.
Merle reported on longer-term data from the KEYNOTE-240 trial after about 1.5 years of additional follow-up since the final analysis and a median follow-up of 40 months (Abstract 268).
A total of 413 patients with confirmed advanced hepatocellular carcinoma who experienced failure (progression or intolerance) to sorafenib therapy were randomized to pembrolizumab 200 mg IV every 3 weeks (278 patients) plus best supportive care (BSC), or placebo (135 patients) plus BSC for 35 cycles or until confirmed progression/unacceptable toxicity, patient withdrawal of consent, or investigator decision.
Dual primary endpoints were OS and PFS, assessed by blinded independent central review per RECIST v1.1. Secondary endpoints included ORR, duration of response (DOR), disease control rate (DCR), time to progression (TTP), and safety.
As of July 13, 2020, median time from randomization to data cutoff was 40 months for both study arms. Median OS was 13.9 months for pembrolizumab and 10.6 months for placebo. Estimated OS rates for pembrolizumab at 24 months (28.8%) and 36 months (20.4%) were higher than for placebo (17.7%, 11.7%). Median PFS was 3.3 months for pembrolizumab and 2.8 months for placebo. Estimated PFS rate at 24 months was 11.8 percent for pembrolizumab and 4.8 percent for placebo. ORR was 18.3 percent for pembrolizumab and 4.4 percent for placebo.
Median time to response was similar in both arms (2.7 months for pembrolizumab and 2.9 months for placebo), as was median DOR (13.9 months for pembrolizumab and 15.2 months for placebo). Nearly half (45.1%) of responders in the pembrolizumab arm and one-third of responders in placebo arm had DOR of 12 months. DCR was slightly higher with pembrolizumab (61.9%) than placebo (53.3%). Best overall responses included 10 CRs and 41 partial responses (PR) for pembrolizumab and zero CRs and six PRs for placebo. The median TTP was 4 months for pembrolizumab and 2.8 months for placebo.
"No new or unexpected adverse events occurred. The frequency of sponsor-assessed immune-mediated hepatitis events did not increase with additional follow-up," said Merle. There continued to be no hepatitis B or C viral flare events.
In conclusion, Merle said: "In sorafenib-treated patients with advanced hepatocellular carcinoma, numeric improvement in OS and PFS was maintained over time with pembrolizumab compared with placebo. The safety profile of pembrolizumab remained consistent over time. These data support the benefit/risk profile of pembrolizumab in patients previously treated advanced hepatocellular carcinoma."
Mark L. Fuerst is a contributing writer.